PROJECT SUMMARY/ABSTRACT Metabolic syndrome refers to the clustering of known cardiovascular risk factors including diabetes, hypertension, obesity, dyslipidemia and other emerging risk factors within an individual. Heart disease still remains the leading cause of death in the world and people with metabolic syndrome are twice as likely to suffer heart attack and five-fold more likely to develop type 2 diabetes. Thus there is a clear need to better treat metabolic syndrome and its related comorbidities. Fibroblast growth factor 21 (FGF21) is an important metabolic regulator and functions, in part, through central activation of the sympathetic nervous system. The activity of sympathetic preganglionic neurons relies on the activity of medullary and supramedullary sites. While the brain stem nuclei, such as the commissural nucleus tractus solitarius and rostral ventrolateral medulla (RVLM) have are integral in cardiovascular regulation, the role of other supramedullary nuclei in FGF21-induced sympathetic activation are still not clear. We have previously characterized the role of the paraventricular nucleus (PVN) of the hypothalamus in the cardiovascular control. Our preliminary data suggest that FGF21 increases cardiovascular-related sympathetic activity and augments the sympathetic baroreflex. Dorsomedial hypothalamic nucleus (DMH) orchestrates the sympathetic activity to stressful conditions. While both the PVN and DMH are known to play an important role in the sympathetic regulation, little is known regarding FGF21 within these hypothalamic nuclei. The purpose of this proposal is to characterize the central neural pathways responsible for FGF21-induced changes in sympathetic activity. Our working hypothesis is that ?FGF21 activates CRH expressing PVN neurons that project to DMH to increase metabolic-related sympathetic activity?. The first specific aim for the proposed research project is to create CRH specific Fr1-/- mouse colony by crossing Crh-IRES-Cre mice with Fr1 floxed mice. Our second specific aim is to identify FGF21 activation of hypothalamic metabolic and cardiovascular related presympathetic neurons. We will identify hypothalamic sympathetically- related neurons by injecting different fluorescent retrograde tracers into either the brain stem center for sympathetic cardiovascular activity or metabolic activity and examining FGF21-induced cFos activation. Lastly, to determine if FGF21 augments reflex sympathetic activity we will perform direct sympathetic nerve recording in the anesthetized rat and record basal and reflex activity from either from nerve fibers innervating either IBAT or splanchnic sympathetic nerve activity. The proposed study will provide much needed information on hypothalamic regulation of the autonomic nervous system and a clearer understanding of the role of the FGF21 in sympathetic control of blood pressure and metabolism. AREA GRANT JUSTIFICATION: These studies employ approaches appropriate for undergraduate research on a poorly understood central metabolic activity. In keeping with the goal to incorporate undergraduates into research, students will be directly involved in assisting or performing surgery, necropsy, and histology in an area of research that most undergraduates get very little exposure. Students will be responsible for discrete units of this research that they take on as independent projects. The investigators have a successful history of incorporating undergraduate students in research projects leading to scientific presentations, Honors theses, and peer-reviewed publications.